Synthesis of nitric oxide gas for inhalation

ABSTRACT

In some additional aspects, an apparatus can include a chamber having an inlet valve for receiving a reactant gas and an outlet valve for delivering a product gas, a piston positioned inside the chamber and configured to move along a length of the chamber for adjusting pressure in the chamber, a sensor for collecting information related to one or more conditions of a respiratory system associated with a patient, a controller for determining one or more control parameters based on the collected information, and one or more pairs of electrodes positioned inside the chamber for initiating a series of electric arcs external to the patient to generate nitric oxide based on the determined control parameters.

CLAIM OF PRIORITY

This application claims the benefit of U.S. Patent Application Ser. No.61/789,161 and U.S. Patent Application Ser. No. 61/792,473, filed onMar. 15, 2013, the entire contents of which are hereby incorporated byreference.

TECHNICAL FIELD

This invention is related to synthesis of nitric oxide gas forinhalation.

BACKGROUND

Nitric oxide (NO) is a crucial mediator of many biological systems, andis known to mediate the control of systemic and pulmonary artery bloodpressure, help the immune system kill invading parasites that entercells, inhibit the division of cancer cells, transmit signals betweenbrain cells, and contribute to the death of brain cells that candebilitate people with strokes or heart attacks. Nitric oxide alsomediates the relaxation of smooth muscle present, for example, in thewalls of blood vessels, bronchi, the gastrointestinal tract, andurogenital tract. Administration of nitric oxide gas to the lung byinhalation has been shown to produce localized smooth muscle relaxationto treat pulmonary hypertension, pneumonia, hypoxemic respiratoryfailure of the newborn, etc. without producing systemic side effects.

Inhaled nitric oxide is a potent local pulmonary vasodilator thatimproves the matching of ventilation with perfusion, thereby increasingthe injured lungs oxygen transport efficiency, and raises the arterialoxygen tension. Breathing nitric oxide combines a rapid onset of actionoccurring within seconds with the absence of systemic vasodilation. Onceinhaled, NO diffuses through the pulmonary vasculature into thebloodstream, where it is rapidly inactivated by combination withhemoglobin. Therefore, the vasodilatory effects of inhaled nitric oxideare limited to the pulmonary vasculature. The ability of nitric oxide todilate pulmonary vessels selectively provides therapeutic advantages inthe treatment of acute and chronic pulmonary hypertension. Inhaled NOhas also been used to prevent ischemia reperfusion injury after PCI inadults with heart attacks Inhaled NO can produce systemicanti-inflammatory and anti-platelet effects by increasing the levels ofcirculating NO biometabolites and other mechanisms.

U.S. Pat. No. 5,396,882 to Zapol, which is incorporated by referenceherein, describes electric generation of nitric oxide (NO) from air atambient pressure for medical purposes. As described in U.S. Pat. No.5,396,882, an air input port of the system is used for continuouslyintroducing air into the region of the electric arc.

SUMMARY

In some aspects, a method includes collecting information related to oneor more conditions of a respiratory system associated with a patient.The method also includes determining one or more control parametersbased on the collected information. The method also includes initiatinga series of electric arcs external to the patient to generate nitricoxide based on the determined control parameters.

Embodiments can include one or more of the following.

The conditions associated with the respiratory system can include one ormore of the oxygen concentration of a reactant gas, a flow rate of thereactant gas, a volume and timing of an inspiration, the oxygenconcentration of a product gas, the nitric oxide concentration of theproduct gas, the nitrogen dioxide concentration of the product gas, theozone concentration of the product gas, the nitric oxide concentrationof an inhaled gas, and the nitrogen dioxide concentration of the inhaledgas.

The volume and timing of an inspiration can be received from aventilator.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide.

The series of electric arcs can generate a reduced level of ozone.

The reduced level of nitrogen dioxide can be further reduced by ascavenger including one or more of KaOH, CaOH, CaCO3, and NaOH.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The series of electric arcs can be generated by electrodes including anoble metal.

The series of electric arcs can be generated by electrodes includingiridium.

The series of electric arcs can be generated by electrodes includingnickel.

In some additional aspects, an apparatus includes a chamber having aninlet valve for receiving a reactant gas and an outlet valve fordelivering a product gas. The apparatus also includes a sensor forcollecting information related to one or more conditions of arespiratory system associated with a patient. The apparatus alsoincludes a controller for determining one or more control parametersbased on the collected information. One or more pairs of electrodes areincluded in the apparatus and positioned inside the chamber forinitiating a series of electric arcs external to the patient to generatenitric oxide based on the determined control parameters.

Embodiments can include one or more of the following.

The conditions associated with the respiratory system can include one ormore of the oxygen concentration of the reactant gas, a flow rate of thereactant gas, a volume and timing of an inspiration, the oxygenconcentration of the product gas, the nitric oxide concentration of theproduct gas, the nitrogen dioxide concentration of the product gas, theozone concentration of the product gas, the nitric oxide concentrationof an inhaled gas, the nitrogen dioxide concentration of the inhaledgas, and the pressure in the chamber.

The volume and timing of an inspiration can be received from aventilator.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide.

The series of electric arcs can generate a reduced level of ozone.

The series of electric arcs can be initiated when the chamber has apressure greater than 1 ATA or less than 1 ATA.

The apparatus can also include a scavenger for further reducing thereduced level of nitrogen dioxide, and the scavenger can include one ormore of KaOH, CaOH, CaCO3, and NaOH.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The electrodes can include a noble metal.

The electrodes can include iridium.

The electrodes can include nickel.

In some additional aspects, an apparatus includes a chamber having aninlet valve for receiving a reactant gas and an outlet valve fordelivering a product gas. The apparatus also includes a pistonpositioned inside the chamber and configured to move along a length ofthe chamber for adjusting pressure in the chamber. The apparatus alsoincludes a sensor for collecting information related to one or moreconditions of a respiratory system associated with a patient. Theapparatus includes a controller for determining one or more controlparameters based on the collected information. One or more pairs ofelectrodes are included and positioned inside the chamber for initiatinga series of electric arcs external to the patient to generate nitricoxide based on the determined control parameters.

Embodiments can include one or more of the following.

The conditions associated with the respiratory system can include one ormore of the oxygen concentration of the reactant gas, a flow rate of thereactant gas, a volume and timing of an inspiration, the oxygenconcentration of the product gas, the nitric oxide concentration of theproduct gas, the nitrogen dioxide concentration of the product gas, theozone concentration of the product gas, the nitric oxide concentrationof an inhaled gas, the nitrogen dioxide concentration of the inhaledgas, and the pressure in the chamber.

The volume and timing of an inspiration can be received from aventilator.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide.

The series of electric arcs can generate a reduced level of ozone.

The series of electric arcs can be initiated when the chamber has apressure greater than 1 ATA or less than 1 ATA.

The apparatus can also include a scavenger for further reducing thereduced level of nitrogen dioxide, and the scavenger can include one ormore of KaOH, CaOH, CaCO3, and NaOH.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The electrodes can include a noble metal.

The electrodes can include iridium.

The electrodes can include nickel.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a block diagram of a respiratory system for producing NO.

FIG. 2 is an example of an NO generator.

FIG. 3 is an example of an NO generator.

FIG. 4 depicts a device for concentrating oxygen.

FIG. 5 depicts a device for cooling a gas.

FIG. 6 is an example of an NO generator.

FIG. 7 is an example of an NO generator.

FIG. 8 is an example of an NO generator.

FIG. 9A is a photograph showing an example of a respiratory system forproducing NO.

FIG. 9B is a photograph of an NO generator.

FIG. 10 depicts a representation of a pulse train and a pulse group.

FIG. 11A shows average current and voltage as a function of sparks persecond.

FIG. 11B shows average power as a function of sparks per second.

FIGS. 12A-B show tracings of voltage and current during two sparks of a1 spark/second discharge.

FIG. 13 shows NO and NO₂ concentrations using various electrodematerials.

FIG. 14 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 15 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 16 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 17 shows ozone levels at various oxygen concentrations.

FIG. 18 shows ozone levels at various oxygen concentrations.

FIG. 19 shows ozone levels at various oxygen concentrations.

FIG. 20 shows ozone levels at various oxygen concentrations.

FIG. 21 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 22 shows a test setup for measuring NO and NO₂ levels in ahypobaric chamber at various atmospheric pressures.

FIG. 23 shows NO and NO₂ levels at various atmospheric pressures.

FIG. 24 is a flowchart.

FIG. 25 illustrates an example of a computing device and a mobilecomputing device that can be used to implement the operations andtechniques described herein.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Synthesis of NO for inhalation is achieved by electrically sparking areactant gas including N₂ and O₂ (e.g., air), thereby forming a productgas including the electrically synthesized NO. The synthesis may beachieved under hypobaric or hyperbaric conditions. As used herein,“hypobaric” generally refers to a pressure less than 1 ATA (atmosphereabsolute), and “hyperbaric” to a pressure greater than 1 ATA. Theproduct gas can include a medically acceptable level of NO₂ (e.g.,usually less than 5 ppm, and sometimes less than 1-2 ppm). The productgas may be inhaled either with or without reducing the concentration ofNO₂ in the product gas. Apparatuses described herein for synthesis ofnitric oxide can be portable, light-weight, self-powered, and can beused to provide product gas for therapeutic use, with a concentration ofNO in the range of 0.5 ppm to 500 ppm and a concentration of NO₂ of lessthan 1% of the NO concentration, or even lower (e.g., less than 1%)after using a scavenger.

FIG.1 shows an example of a respiratory system 100 for producing NO. Areactant gas (e.g., air, or a 10-90% oxygen mixture in nitrogen) entersan NO generator 102, and a product gas (including NO) exits the NOgenerator 102. The NO generator 102 includes electrodes 106 and acontroller 110. If the reactant gas is a gas other than air, the NOgenerator 102 can include an oxygen level sensor 112. NO production isproportional to oxygen and nitrogen concentration and maximal at about50% oxygen at atmospheric pressure (1 ATA). The oxygen level sensor 112can be an electrode configured to detect a concentration of oxygen inthe reactant gas, as described in more detail below. The electrodes 106generate sparks in the presence of the reactant gas to produce NO 104,as described herein.

FIG. 2 shows an example of an NO generator 200. NO generator 200includes chamber 202 having inlet valve 204 and outlet valve 206. Insome cases, filter 208 is coupled to NO generator 200, such that agaseous mixture including N₂ and O₂ entering chamber through inlet valve204 is filtered to remove particulate matter (e.g., dust) or watervapor. Chamber 202 includes electrodes 210. Electrodes 210 are separatedby a gap, and one of the electrodes is coupled to voltage source 212.Voltage source 212 is suitable to create a spark or corona dischargecapable of forming NO from N₂ and O₂ between electrodes 210. Examples ofvoltage source 212 include, but are not limited to, a piezoelectriccrystal, a battery (e.g., a motorcycle battery), a solar cell, a windgenerator, or other source suitable to produce a current on the order ofnanoamperes or milliamperes and a voltage of 1 to 25 kV (e.g., a powerof 1 to 100 watts), or a voltage of 1 to 10 kV or 1 to 5 kV.

When NO generator 200 is used for hypobaric or hyperbaric synthesis ofNO, chamber 202 may be a cavity in a positive displacement pump. Asshown in FIG. 2, chamber 202 may be a cavity in a piston pump and has avariable volume defined by the position of piston 214 in barrel 216.Piston 214 is coupled to actuator 218. In one example, actuator 218includes an eccentric mechanism driven by a rod or shaft. Actuator 218is driven by prime mover 120 in a reciprocating manner. Prime mover 220may be, for example, a motor or engine (e.g., an electric or gasoline ordiesel powered engine) arranged to translate piston 214 with respect tobarrel 216 by way of actuator 218. Seal 222 inhibits the flow of airinto or out of chamber 202 between piston 214 and barrel 216. Thus, whenboth inlet valve 204 and outlet valve 206 are closed, translation ofpiston 214 away from electrodes 210 by actuator 218 increases the volumeof chamber 202, thereby reducing the pressure in chamber 202 to apressure below atmospheric pressure and reducing a concentration ofgases (e.g., N₂ and O₂) in a reactant gas present in the chamber.Conversely, translation of piston 214 toward the electrodes 210 byactuator 218 decreases the volume of chamber 202, thereby increasing thepressure in chamber 202 to a pressure above atmospheric pressure andincreasing the pressure and concentration of gases in a reactant gaspresent in the chamber. Because NO production is proportional to oxygenconcentration, the pressure of the chamber 202 can have an effect on theproduction of NO. For example, when the chamber 202 has a relativelyhigh pressure (e.g., 2 ATA), NO production is increased.

Inlet valve 204 may be exposed to the environment such that, with theinlet valve open, ambient air (or other reactant gas containing N₂ andO₂) enters chamber 202. With air in chamber 202, inlet valve is closedand piston 214 translates away from electrodes 210, thereby increasingthe volume of chamber 202 and decreasing the pressure inside chamber 202to a pressure below atmospheric pressure. As the volume of chamber 202increases, the concentration of O₂ in the chamber falls below theconcentration of O₂ in air at atmospheric pressure (e.g., falls below 21vo l %). Actuator 218 may be controlled to increase a volume of chamber202 by a factor of 2, 3, 4, etc., thereby reducing a pressure in chamber202 to a fraction (e.g., ½, ⅓, ¼, etc.) of atmospheric pressure. Whilethe pressure in chamber 202 is below atmospheric pressure, voltagesource 212 initiates sparks or corona discharges across electrodes 210,thereby electrically generating NO. Following the sparks or coronadischarges, actuator 218 continues its reciprocating cycle, and outletvalve 206 is opened to release the product gas containing theelectrically generated NO. Thus, inlet valve 204 and outlet valve 206operate out of phase with each other, such that outlet valve 206 isclosed when inlet valve 104 is open, and inlet valve 204 is closed whenoutlet valve 206 is open.

Conversely, with air in chamber 202, inlet valve is closed and piston214 translates toward the electrodes 210, thereby decreasing the volumeof chamber 202 and increasing the pressure inside chamber 202 to apressure above atmospheric pressure. As the volume of chamber 202decreases, the pressure (concentration) of O₂ in the chamber rises abovethe pressure (concentration) of O₂ in air at atmospheric pressure (e.g.,rises above 21 vol %). Actuator 218 may be controlled to decrease avolume of chamber 202 to a fraction of ½, ⅓, ¼, etc., thereby increasinga pressure in chamber 202 to 2, 3, 4, etc. times atmospheric pressure.While the pressure in chamber 202 is above atmospheric pressure, voltagesource 212 initiates sparks or corona discharges across electrodes 210,thereby electrically generating NO.

In some examples, electrodes in an NO generator (e.g., electrodes 210)can be duplicated for safety purposes to provide a spare. The electrodes210 can be doubled or tripled for increased power and NO production withlarge tidal volumes. Referring briefly to FIG. 13, the electrodes 210can contain iridium, tungsten, stainless steel, or nickel, to name afew. In some examples, electrodes 210 that contain a noble metal (e.g.,iridium) produce the smallest ratio of NO₂/NO.

FIG. 3 shows an example of an NO generator 300. NO generator 300includes components of NO generator 200, as described with respect toFIG. 2, with source 302 coupled to inlet valve 204 and arranged toprovide a reactant gas to chamber 202. In some instances, source 302 isan apparatus arranged to provide a reactant gas with a concentration ofO₂ less than 21 vol % or less than 20 vol %. In some instances, source302 is an apparatus arranged to provide a reactant gas with aconcentration of O₂ more than 21 vol % but not more than 90 vol %. Forexample, source 302 may include a cylinder of N₂ or an inert gas (e.g.,argon or helium) and a mechanism to mix the N₂ or inert gas with air oran enriched oxygen containing source at a selected ratio to achieve adesired concentration of O₂, N₂, and/or other components in the reactantgas provided to chamber 202. In some examples, an oxygen cylinder, anoxygen concentration, or an oxygen generator is used to raise theconcentration of oxygen in the reactant gas. The reactant gas istypically provided to chamber 202 at a pressure of 1 ATA (atmosphereabsolute) or above (e.g., slightly above, to 3 ATA) to avoid admixtureof the reactant gas with air. Before entering chamber 202, reactant gasfrom source 302 may pass through an equilibrium bag 304, held slightlyabove atmospheric pressure. Blow-off valve 306 may be present to allowthe pressure of the reactant gas to be maintained close to atmosphericpressure.

In some instances, source 302 includes an oxygen concentrator, oxygengenerator, or oxygen cylinder. FIG. 4 depicts an oxygen concentrator400, in which pressurized air enters oxygen concentrator 400 throughinlet 402 and passes through molecular sieve 404, yieldingoxygen-enriched gas (e.g., having at least 30 vol % or 50 vol % O₂). Theexhaust gas, which has an O₂ concentration less than that of ambient airand a N₂ concentration greater than that of ambient air, exits oxygenconcentrator 400 through valve 406, and is provided to the inlet valve204.

In some instances, source 302 includes an apparatus for cooling air(e.g., a copper tube heat exchanger), such that air at a temperatureless than room temperature (e.g., a temperature approaching 0° K) isprovided to chamber 202 through valve 204, and the spark or coronadischarge occurs in a cooled reactant gas having a temperature less thanroom temperature. Source 302 may operate to cool air by refrigeration orheat exchange methods generally known in the art. FIG. 5 depicts oneexample of a cooling device 500, in which air or another reactant gas(e.g., a mixture of air and N₂ or an inert gas, such as argon, helium,or the like) flows through coil 502 and is cooled by coolant 504, whichenters chamber 506 through inlet 508 and exits the chamber throughoutlet 510. Coil 502 may be a heat-conductive tubing such as, forexample, copper tubing. Coolant 504 may be, for example, liquid N₂ or acycling refrigerant (e.g., chlorofluorocarbon or hydro chlorofluorocarbon).

In certain instances, one or more implementations of source 302 asdescribed above with respect to FIG. 3 are combined to form a gaseousmixture. For example, source 302 may include a cylinder of N₂ or aninert gas (e.g., argon or helium) and a mechanism to mix the N₂ or inertgas with air at a selected ratio to achieve a desired concentration ofO₂ as measured, for example, with a sensor including an electrode, aswell as an apparatus to cool the reactant gas before the reactant gas isprovided to chamber 202. An apparatus to cool the reactant gas may coolthe reactant gas at more than one location (e.g., at the regulator orcylinder head of a gas cylinder, at valve 204, and the like).

In other embodiments, as shown in FIG. 6, an NO generator 600 includesconstant volume chamber 602. In some cases, inlet valve 204 is exposedto the environment such that, with the inlet valve open, ambient airenters chamber 602 (e.g., through filter 208). Inlet valve 204 andoutlet valve 206 may be synchronized such that a gaseous mixture flowsinto chamber 602 through inlet valve 204, and the inlet valve is closedbefore the sparks or corona discharges are initiated. Outlet valve 206is typically closed while inlet valve 204 is open, and may open priorto, during, or after initiation of the sparks or corona discharges. Incertain cases, constant volume chamber 602 is coupled to source 302, andreactant gas is provided to chamber 602 by source 302. Filter 208 may bepositioned between source 302 and chamber 602 (e.g., between source 302and equilibrium bag 304, as illustrated, or between blow-off valve 306and inlet valve 204, as shown in FIG. 3). The exhaust of an oxygenconcentrator may be used to provide a reactant gas having a decreased O₂content to chamber 602. NO generator 600 may be operated in anenvironment having an ambient pressure less than 1 ATA (e.g., at highaltitude). Alternatively, constant volume 602 chamber is coupled to pump604 through valve 606. Pump 604 may be, for example, a positivedisplacement pump such as a lobe pump or a vane pump, arranged todecrease the gas pressure in chamber 602, thereby decreasing theconcentration of O₂ and N₂ in the reactant gas in chamber 602.Similarly, pump 604 can be arranged to increase the gas pressure inchamber 602, thereby increasing the concentration of O₂ and N₂ in thereactant gas in chamber 602 to achieve higher levels of NO generation.

FIG. 7 shows an example of an NO generator 700. NO generator 700includes components of NO generator 500, as described with respect toFIG. 6, with source 302, as described with respect to FIG. 3, coupled toinlet valve 204 and arranged to provide a reactant gas to chamber 602.As noted with respect to FIG. 6, NO may be selectively synthesized inchamber 602 at ambient pressure, at a reduced pressure, or at anincreased pressure achieved with pump 604.

The product gas that exits chamber 202 or 602 through outlet valve 206of NO generator 200, 300, 600, and 700 includes the electricallygenerated NO, and may include low levels of NO₂ and O₃. In some cases,the product or effluent gas can be gauged to a piston to raise thepressure of the produced gas for injection into a ventilator, or coupledto an endotracheal tube for continuous injection or injection coupledwith inspiration and proportional to airway flow. The product gas can bestored briefly at atmospheric pressure (e.g., stored for seconds beforedirect inhalation by a patient through a mask, before injection into anairstream for ventilation, or before use thereof to drive a ventilator).The product gas can be admixed in ventilator gases. In certain cases,the product gas may be treated to reduce a concentration of one or morecomponents in the gas. In one example, the product gas is combined withambient or pressurized air or oxygen to yield a lower effectiveconcentration of NO. In some examples, the product gas is treated toremove one or more unwanted by-products (e.g., NO₂ and O₃) by contactingthe product gas with a scavenger (e.g., scavenger 226). In someexamples, the scavenger 226 includes one or more of KaOH, CaOH, CaCO₃,and NaOH.

Referring to FIG. 2, the scavenger 226 can be placed in a cartridge 228to process produced gas exiting the outlet valve 206. The cartridge 228,the scavenger 226, or both may be replaceable due to the limitedabsorption capabilities of the scavenger material. The scavenger 226 canindicate its extent of absorption (i.e., how close the scavenger is tomaximum absorption) by changing color. In some examples, at aconcentration of 80 ppm NO in the product gas, a scavenger 226 having avolume of 100m1 can reduce the concentration of NO₂ to about 0 ppm.

In certain cases, including implementations of NO generator 300 and 700in which exhaust gas from an oxygen concentrator is used for hypobaricsynthesis of NO, the product gas that exits chamber 202 or 602 throughoutlet valve 206 may be combined with O₂-enriched air from the oxygenconcentrator or pure O₂ from a source to form a gaseous mixtureincluding a medically effective level of NO in O₂-enriched air, with lowlevels of NO₂. One or more methods of treating the product gas can becombined in any order such that, for example, NO₂ is removed from aproduct gas that exits chamber 202 or 602 through outlet valve 206 toyield a gaseous mixture, and this gaseous mixture is then combined withO₂-enriched air from an oxygen concentrator, or a product gas that exitschamber 202 or 602 through outlet valve 206 is combined with O₂-enrichedair from an oxygen concentrator to form a gaseous mixture, and NO₂ isthen removed from the gaseous mixture. The final mixture can be againsubjected to scavenging to remove NO₂.

In some instances, the concentration of one or more components in theproduct gas can be adjusted by varying the flow of gas through the inletvalve, varying the spark or discharge frequency, varying the voltage orcurrent supplied to the electrodes, as described in more detail below,or adding multiple series of sparking electrodes.

FIG. 8 depicts a respiratory system 800 for electric synthesis of NO inwhich product gas from output valve 206 of NO generator 802 is providedto monitor 804. The monitor 804 can collect information related to oneor more conditions associated with the respiratory system. NO generator802 may be any NO generator described herein. Monitor 804 may includeone or more sensors for assessing a concentration of one or morecomponents in the product gas. In some examples, the sensors useelectrodes, chemiluminescent, or UV absorption means to measure theconcentration of NO, NO₂, O₃, O₂, or any combination thereof. In somecases, monitor 804 provides feedback to NO generator 802 or source 302to adjust production of NO, decrease production of NO₂ or O₃, etc. Forinstance, an assessed concentration of NO is used to adjust the flow orconcentration of reactant gas or a gas to be mixed with the reactant gas(e.g., N₂, an inert gas, air, or O₂) into the chamber (e.g., chamber 202or 602), the electrode size, spacing, or temperature, the sparkfrequency, or voltage, peak current, or limiting current of an NOgenerator. In one example, if an assessed concentration of NO is higherthan desired, the flow of gas into the chamber can be increasedaccordingly, thereby reducing the concentration of NO in the productgas. In some examples, a gas pump causes the gas to flow into thechamber. The monitor 804 can include a gas flow sensor for measuring theflow rate of the gas entering the chamber.

As described herein, an NO generator produces gas for respiration with aconcentration of NO between 0.5 ppm and 500 ppm (e.g., at least 0.5 ppmand up to 1 ppm, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm, or 500 ppm). Theproduced gas may be diluted before inhalation. The gas can be used tooxidize hemoglobin ex vivo (e.g., in a stored blood transfusion) orinhaled by adults, children, or newborns to therapeutically treatrespiratory disorders by selective pulmonary vasodilation, includingpulmonary fibrosis, infection, malaria, myocardial infarction, stroke,pulmonary hypertension, persistent pulmonary hypertension newborns, andother conditions in which breathing NO to oxidize hemoglobin or todeliver NO metabolites into the circulation is valuable. In some cases,the NO generator can be used to supply gas for breathing to humansexperiencing pulmonary hypertension and hypoxia as a result of explosivedecompression of an aircraft or spacecraft, to treat high altitudepulmonary edema, and/or to treat any medical condition at high altitudeby sparking or corona discharge of air in a hypobaric environment, withadvantages including rapid, hypobaric synthesis of a breathabletherapeutic gas including NO in the absence of gas cylinders.

In some embodiments, for example when an NO generator is used to provideinput to a ventilator, the operation of the NO generator (e.g., thetiming and frequency of the spark or corona discharge, the opening andclosing of the inlet valve and the outlet valve, and the like) issynchronized with the inspiratory pressurization or gas flow in theairway (e.g., as measured by a hot wire anemometer or pneumotachograph),such that the necessary quantity of NO supplemented gas for respirationis produced and injected when needed. This coordinated production of NOfor medical uses provides the additional advantage that NO is breathedas it is produced in an oxygen containing gas mixture, allowing lesstime for NO to oxidize to NO₂ before inhalation. When NO is produced, itonly lasts for a short period time. After the short period of time, itbegins to oxidize into NO₂ which, when dissolved in water, forms nitricacid and nitrate salts. If NO is produced long before a user is ready toinhale it, the NO can be oxidized into these toxic products at the timeof inspiration. The nitric acid and nitrate salts can damage componentsof the NO generator as well as the lungs. In combination withspontaneous ventilation, inhalation can be tracked by the EMG of thediaphragm, or a thoracic or abdominal impedance belt, or various airwayflow sensors, or taken directly from the ventilator software triggeringprogram, and the electrically generated NO can be injected in therespiratory gas at the onset of inspiration via the nose or trachea witha tube or mask.

FIG. 9A shows an example of a respiratory system 900 for producing NO.In some embodiments, NO is produced electrically under ambientconditions, or hypobaric or hyperbaric conditions. The respiratorysystem 900 includes power supply 902 and chamber 904. Various components(e.g., an oscilloscope) can make electrical measurements of therespiratory system 900. In some embodiments, power supply 902 is abattery, and the respiratory system 900 is portable and wearable. FIG.9B shows an example of an NO generator 916 of respiratory system 900.Reactant gas is provided to chamber 904 through inlet 908, and productgas exits chamber 904 via outlet 910. Power supply 902 is coupled toelectrodes 906 in chamber 904 to generate sparks therebetween. Powersupply 902 may be operatively coupled to pulse generator 912. Sparksacross electrodes 906 form NO in chamber 904 as described herein. For anNO generator such as NO generator 916, a 1 kV to 10 kV spark acrosselectrodes 906 for 10-30 milliseconds that has microampere current,requiring less than 20 W or less than 10 W, based on averaging over thelength of the duration of the pulse. Averaging the power consumptionover a longer time (e.g., a second) would yield a lower average powerconsumption (e.g., an order of magnitude or two lower, or about 0.1 W to1 W).

Systems for producing NO described herein, including respiratory system900 and others, may also include a controller 914. The controller 914coordinates triggering of a voltage source to deliver a series ofelectrical pulses to the electrodes (e.g. electrodes 806), therebygenerating NO. The electrodes may be composed of or plated with amaterial that is capable of optimally producing NO with minimal unwantedtoxic by-products. In some examples, the electrodes include a noblemetal such as iridium. The controller 914 can be coupled to the pulsegenerator 912 and at least a portion of the NO generator 916 (e.g., theelectrodes 906) and can control parameters such as spark frequency,spark duration, and the like to generate the needed amount of NO andminimum amount of unwanted toxic by-products (e.g., NO₂, O₃).

The controller 914 can be configured to receive information from one ormore sensors in the respiratory system 900. The controller 914 can usethe information received from the sensors to determine one or morecontrol parameters for the respiratory system 900. For example, readingsfrom the oxygen level sensor 112 can be used by the controller 914 todetermine the one or more control parameters. The respiratory system 900can include a tidal volume or respiratory gas flow sensor (e.g., athermistor, a hot wire anemometer) for measuring the volume, timing, andoxygen concentration of inspired gas. The controller may receiveinformation from the ventilator related to ventilatory time ofinspiration or inspired oxygen concentrations . In some examples, thecontroller 914 can determine control parameters based on one or more of:i) information received from a monitor (e.g., monitor 804 of FIG. 8 forassessing the concentration of components in the product gas orventilator, such as the NO and NO₂ concentration; ii) concentration ofcomponents in the reactant gas (e.g., oxygen concentration); iii)operating parameters of the NO generator 900; iv) pressure in thechamber 202 (e.g., especially for embodiments where the NO generator200, 300 includes a piston 214 for adjusting pressure in the chamber202); v) flow rate of the reactant gas; vi) actual or expected volume ofan inspiration, and vii) whether the produced NO will be diluted withother respiratory gases (e.g., oxygen), to name a few.

The NO generator 900 can provide all or a portion of the product gas atthe extremely high breathing frequency of a High Frequency OscillatoryVentilator (HFOV). The NO generator 900 can provide all or a portion ofthe product gas to a positive pressure ventilator, an anesthesiamachine, a continuous positive airway pressure apparatus, or a manualresuscitator, to name a few.

Adult humans normally breathe from 10-20 times per minute, each breathhaving a duration of 3-6 seconds. Typically, about one half to one thirdof the breath's duration is inspiration. On average, each breath has atidal volume of about 500 ml. In children, each breath typically hasless volume, but breathing occurs at a higher rate. Thus, in the averageadult, about 10-20 breaths per minute with 1 second inspirations allowintervals for spark generation of about 10 seconds per minute.

The expected volume of an inspiration can be calculated using previoustidal volume measurements. For example, the controller 914 may determinethat the expected tidal volume of a subsequent inspiration is going tobe the same as the tidal volume measurement for the most recentinspiration. The controller 914 can also average the tidal volumes ofseveral prior inspirations to determine the expected tidal volume of asubsequent inspiration. In some examples, the controller 914 can obtainan expected tidal volume value from the ventilator.

Implementations of controller 914 can include digital electroniccircuitry, or computer software, firmware, or hardware, including thestructures disclosed in this specification and their structuralequivalents, or combinations of one or more of them. An optical orelectrical sensor can be incorporated into the device to observe andreport the occurrence of the spark(s), and give an alarm if the sparksare not occurring. For example, controller 914 can be a microprocessorbased controller (or control system) as well as an electro-mechanicalbased controller (or control system). Instructions and/or logic in thecontroller can be implemented as one or more computer programs, i.e.,one or more modules of computer program instructions, encoded oncomputer storage medium for execution by, or to control the operationof, data processing apparatus. Alternatively or in addition, the programinstructions can be encoded on an artificially generated propagatednon-transitory signal, e.g., a machine-generated electrical, optical, orelectromagnetic signal that is generated to encode information fortransmission to suitable receiver apparatus for execution by a dataprocessing apparatus.

Controller 914 can include clients and servers and/or master and slavecontrollers. A client and server are generally remote from each otherand typically interact through a communication network. The relationshipof client and server arises by virtue of computer programs running onthe respective computers and having a client-server relationship to eachother. In some aspects, controller 914 represents a main controller(e.g., master) communicably coupled through communication elements(e.g., wired or wireless) with each of the components of an NOgenerator. Controller 914 may be configured to adjust parameters relatedto duration and frequency of the spark based at least in part on thecomposition of the product gas produced in the chamber.

FIG. 10 shows a representation of a pulse train 1000 that is triggeredby the controller 914. The controller 914 can determine one or morecontrol parameters to create a pulse train. FIG. 10 also shows zoomed inview of one of the pulse groups 1002 of the pulse train 1000. Electricalpulses are delivered to the electrodes (e.g., electrodes 906), and theelectrodes 906 generate a series of sparks (sometimes referred to aselectric arcs). The timing of the pulses (and of the resulting sparks)is controlled by the controller 914, and can be optimized to produce theneeded amount of NO while producing minimal NO₂ and O₃. In someexamples, the controller 914 causes a greater amount of NO to beproduced if the NO will subsequently be diluted with other respiratorygases (e.g., oxygen). Multiple sparks make up a pulse group, andmultiple pulse groups make up the pulse train. Thus, the pulse train1000 initiates the series of electric arcs.

Variables B and N control the overall energy that is created by theelectrodes 906. Variable N sets the number of sparks per pulse group,and variable B sets the number of pulse groups per second. The valuesfor B and N influence the amount of NO, NO₂, and O₃ that is created. Thevalues for B and N also influence how much heat is produced by theelectrodes 806. Larger values of either B or N create more NO and causethe electrodes 906 to produce more heat.

Variables E, F, H, and P control the timing of the sparks produced ineach pulse group. Variable H is the high time of a pulse (e.g., theamount of time the voltage source is activated for each electricalpulse). The high time is sometimes referred to as the pulse width. Hightime and pulse width can be visually represented in a graph of a voltageof a pulse over a period of time. The high time and the pulse width aremeasured from the time the voltage of the pulse exceeds a voltagethreshold until the time the voltage of the pulse falls below thevoltage threshold, and are generally in the order of microseconds.

The longer the voltage source is activated for a particular electricpulse, the larger the visual representation of the width of theparticular electric pulse.

P is the amount of time between pulses. Thus, P minus H represents aperiod of time when no pulses occur (e.g., the voltage source is notactive). Larger values of H and smaller values of P result in theelectrodes 906 producing more energy. When the electrodes 906 create aspark, plasma is established. The temperature of the plasma isproportional to the amount of energy produced by the electrodes 906. Insome examples, for plasma to be produced, the reactant gas has bothnitrogen and oxygen content.

B is typically in the range of 5-80 pulse groups per second, N istypically in the range of 1-50 sparks per pulse group, P is typically inthe range of 10-800 microseconds, and H is typically in the range of5-600 microseconds.

The chemical reactions that cause NO and NO₂ to be produced are afunction of plasma temperature. That is, higher plasma temperaturesresult in more NO and NO₂ being produced. However, the relativeproportions of the produced NO and NO₂ vary across different plasmatemperatures. In some examples, the sparks generated by the first twopulses in a pulse group establish the plasma. The first two sparks canhave a high time that is longer than the sparks produced by the rest ofthe pulses in the pulse group. The amount of time that the first twopulses are extended is represented by variables E and F, respectively.Sparks generated by pulses beyond the first two pulses require lessenergy to maintain the plasma, so the high time of subsequent pulses(represented by variable H) can be shorter to prevent the plasmatemperature from getting too high. For instance, while a relatively highplasma temperature may result in more NO and NO₂ being produced, therelatively high plasma temperature may not be ideal for producing thedesired proportions of NO and NO₂. The material of the electrodes 906can play a major role in determining the amount of energy needed togenerate a particular spark, thus affecting the ratio of NO₂/NOproduced. In some examples, tungsten electrodes produce a relativelyhigh ratio of NO₂/NO, nickel electrodes produced a lower ratio ofNO₂/NO, and iridium electrodes produce an even lower ratio of NO₂/NO, asshown in FIG. 13.

Each spark that is generated creates a particular amount of NO. The NOis diluted in the volume of gas that is produced. To ensure theconcentration of NO in the inspired gas is at the expected level, thecontroller 914 receives information from the tidal volume sensormentioned above to determine control parameters for maintaining anappropriate inspired NO concentration.

The controller 914 may be configured to communicate with the NOgenerator wirelessly (e.g., via Bluetooth). The controller 914 can alsobe configured to communicate with external devices (e.g., a computer,tablet, smart phone, or the like). The external devices can then be usedto perform functions of the controller 914 or to aid the controller 914in performing functions.

In some examples, the controller 914 can disable certain components ofthe NO generator during, before or after a series of sparks isgenerated. In some examples, the controller 914 can also includefeatures to: i) detect and cease unintended sparks; ii) confirm that aseries of sparks is safe before triggering the series of sparks; iii)verify that timing values are checked against back-up copies of timingvalues after every series of sparks is generated to detect timingvariable corruption; and iv) determine whether back-up copies of timingvariables are corrupt.

Results achieved with an NO generator (e.g., NO generator 916) aredescribed with respect to FIGS. 11 through 13.

FIG. 11A is an average current and voltage chart 1100 that shows theaverage current and voltage vs. sparks/second for NO generator 916. FIG.11B is an average power chart 1102 that shows the average power vs.sparks/second for NO generator 916. Average current and power peakbetween 0.5 and 2 sparks/second, and average voltage dips over the samerange. FIG. 12A shows oscilloscope traces 1200 for voltage (upper trace)and current (lower trace) during 2 sparks of a 1 spark/second discharge.FIG. 12B shows oscilloscope traces 1202 for voltage (upper trace) andcurrent (lower trace) traces for a 1 spark/second discharge with a sparkduration (single spark) of 27 msec.

FIG. 13 shows NO and NO₂ concentrations from an NO generator (e.g., NOgenerator 916 of FIG. 9B) using various electrode materials. The testconditions included the use of a ¼″ rod, an electrode gap of 2.0 mm,constant air flow at 5 L/min, and a FiO₂ of 0.21. For the tungstenelectrode, B=40 pulse groups per second, N=30 sparks per pulse group,P=100 microseconds, and H=20 microseconds . For the nickel electrodes,B=35 pulse groups per second, N=40 sparks per pulse group, H=180microseconds, and P=70 microseconds. For the iridium electrodes, B=35pulse groups per second, N=40 sparks per pulse group, H=180microseconds, and P=80 microseconds.

FIG. 14 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using mini spark plug (Micro ViperZ3 with 6 mm HEX and 10-40 THRD, Rimfire, Benton City, Wash.) that iscontinuously sparking.

FIG. 15 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using iridium spark plug (ACDelco41-101, Waltham, Mass.) that are continuously sparking.

FIG. 16 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using iridium spark plug withintermittent sparking.

Ozone (O₃) is a powerful oxidant that has many industrial and consumerapplications related to oxidation. However, its high oxidizing potentialcauses damage to mucus membranes and respiratory tissues in animals.This makes ozone a potent respiratory hazard and pollutant near groundlevel. Ozone is formed from atmospheric electrical discharges, andreacts with NO to form nitric dioxide (NO₂) and O₂ or reacts with N₂ toproduce NO and O₂. In some examples, ozone levels are greater withcontinuous sparking than with intermittent sparking, and also increasewith increasing O₂ concentrations.

FIG. 17 shows O₃ levels at various O₂ concentrations using mini sparkplug and iridium spark plug with continuous sparking. In this example,B=60 pulse groups per second, N=50 sparks per pulse group, P=140microseconds, H=40 microseconds, and air flow rate is 5 L/min.

FIG. 18 shows O₃ levels at various O₂ concentrations using mini sparkplug and iridium spark plug with intermittent sparking triggered on eachbreath commencing with inspiration, or shortly before inspiration began.In this example, B=60 pulse groups per second, N=50 sparks per pulsegroup, P=140 microseconds, H=40 microseconds, and air flow rate is 5L/min.

FIG. 19 shows O₃ levels at various O₂ concentrations using mini sparkplug and iridium spark plug with continuous sparking. In this example,B=35 pulse groups per second, N=25 sparks per pulse group, P=240microseconds, H=100 microseconds, and air flow rate is 5 L/min.

FIG. 20 shows O₃ levels at various O₂ concentrations using mini sparkplug and iridium spark plug with intermittent sparking triggered on eachbreath commencing with inspiration, or shortly before inspiration began.In this example, B=35 pulse groups per second, N=25 sparks per pulsegroup, P=240 microseconds, H=100 microseconds, and air flow rate is 5L/min.

FIG. 21 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations using an oxygen concentrator. In this example, B=5 pulsegroups per second, N=25 sparks per pulse group, P=200 microseconds, H=60microseconds, and air flow rate is 5 L/min.

FIG. 22 shows a test setup for measuring NO and NO₂ levels in ahypobaric chamber 2200 at various atmospheric pressures. The results ofthe test are shown in FIG. 23. To create a negative pressure (e.g., ½ATA, ⅓ ATA) inside the hypobaric chamber 2200, inlet and outlet valveswere closed and a piston translated away from the spark plug. The sparkplug was then fired for 30 seconds. In this example, B=100 pulse groupsper second, N=10 sparks per pulse group, P=140 microseconds, and H=10microseconds. The piston was then translated toward the spark plug tobring the pressure in the hypobaric chamber 2200 back to 1 ATA. Theoutlet valve was opened, and gas samples were collected in a 3 Lrespiratory bag by further translating the piston toward the spark plug.The collected gas samples were analyzed with Sievers NOA i280immediately after collection.

Referring to FIG. 24, a flowchart 2400 represents an arrangement ofoperations of the controller (e.g., controller 914, shown in FIG. 9A).Typically, the operations are executed by a processor present in thecontroller. However, the operations may also be executed by multipleprocessors present in the controller. While typically executed by asingle controller, in some arrangements, operation execution may bedistributed among two or more controllers.

Operations include collecting 2402 information related to one or moreconditions of a respiratory system associated with a patient. Forexample, one or more sensors of the monitor 804 of FIG. 8 can collectinformation related to one or more conditions of the respiratory system.In some examples, other sensors in the respiratory system collectinformation related to one or more conditions of the respiratory system.The conditions associated with the respiratory system include one ormore of the oxygen concentration of an input gas (e.g., reactant gas),an input flow rate of the reactant gas, a gas volume and frequency of aninspiration, the pressure in a chamber of the respiratory system, andthe oxygen concentration of a product gas before and after admixture inthe respiratory system. Operations also include determining 2404 one ormore control parameters based on the collected information. For example,the controller 914 of FIG. 9A can determine one or more controlparameters. The control parameters may create a pulse train. Operationsalso include initiating 2406 a series of electric arcs external to thepatient to generate nitric oxide based on the determined controlparameters. For example, the electrodes 906 of FIG. 9B can initiate aseries of electric arcs external to the patient to generate nitric oxidebased on the determined control parameters. The control parameters maycontrol the timings of the series of electric arcs. In some examples,the conditions associated with the respiratory system also include theamounts of NO and NO₂ generated by the series of electric arcs (e.g.,amounts of NO and NO₂ previously generated).

FIG. 25 shows an example of example computer device 2500 and examplemobile computer device 2550, which can be used to implement theoperations and techniques described herein. For example, a portion orall of the operations of a controller (e.g., controller 914 of FIG. 9A)may be executed by the computer device 2500 and/or the mobile computerdevice 2550. Computing device 2500 is intended to represent variousforms of digital computers, including, e.g., laptops, desktops,workstations, personal digital assistants, servers, blade servers,mainframes, and other appropriate computers. Computing device 2550 isintended to represent various forms of mobile devices, including, e.g.,personal digital assistants, tablet computing devices, cellulartelephones, smartphones, and other similar computing devices. Thecomponents shown here, their connections and relationships, and theirfunctions, are meant to be examples only, and are not meant to limitimplementations of the techniques described and/or claimed in thisdocument.

Computing device 2500 includes processor 2502, memory 2504, storagedevice 2506, high-speed interface 2508 connecting to memory 2504 andhigh-speed expansion ports 2510, and low speed interface 2512 connectingto low speed bus 2514 and storage device 2506. Each of components 2502,2504, 2506, 2508, 2510, and 2512, are interconnected using variousbusses, and can be mounted on a common motherboard or in other mannersas appropriate. Processor 2502 can process instructions for executionwithin computing device 2500, including instructions stored in memory2504 or on storage device 2506 to display graphical data for a GUI on anexternal input/output device, including, e.g., display 2516 coupled tohigh speed interface 2508. In other implementations, multiple processorsand/or multiple buses can be used, as appropriate, along with multiplememories and types of memory. Also, multiple computing devices 2500 canbe connected, with each device providing portions of the necessaryoperations (e.g., as a server bank, a group of blade servers, or amulti-processor system).

Memory 2504 stores data within computing device 2500. In oneimplementation, memory 2504 is a volatile memory unit or units. Inanother implementation, memory 2504 is a non-volatile memory unit orunits. Memory 2504 also can be another form of computer-readable medium,including, e.g., a magnetic or optical disk.

Storage device 2506 is capable of providing mass storage for computingdevice 2500. In one implementation, storage device 2506 can be orcontain a computer-readable medium, including, e.g., a floppy diskdevice, a hard disk device, an optical disk device, or a tape device, aflash memory or other similar solid state memory device, or an array ofdevices, including devices in a storage area network or otherconfigurations. A computer program product can be tangibly embodied in adata carrier. The computer program product also can contain instructionsthat, when executed, perform one or more methods, including, e.g., thosedescribed above. The data carrier is a computer- or machine-readablemedium, including, e.g., memory 2504, storage device 2506, memory onprocessor 2502, and the like.

High-speed controller 2508 manages bandwidth-intensive operations forcomputing device 2500, while low speed controller 2512 manages lowerbandwidth-intensive operations. Such allocation of functions is anexample only. In one implementation, high-speed controller 2508 iscoupled to memory 2504, display 2516 (e.g., through a graphics processoror accelerator), and to high-speed expansion ports 2510, which canaccept various expansion cards (not shown). In the implementation,low-speed controller 2512 is coupled to storage device 2506 andlow-speed expansion port 2514. The low-speed expansion port, which caninclude various communication ports (e.g., USB, Bluetooth®, Ethernet,wireless Ethernet), can be coupled to one or more input/output devices,including, e.g., a keyboard, a pointing device, a scanner, or anetworking device including, e.g., a switch or router, e.g., through anetwork adapter. Computing device 2500 can be implemented in a number ofdifferent forms, as shown in the figure. For example, it can beimplemented as standard server 2520, or multiple times in a group ofsuch servers. It also can be implemented as part of rack server system2524. In addition or as an alternative, it can be implemented in apersonal computer including, e.g., laptop computer 2522. In someexamples, components from computing device 2500 can be combined withother components in a mobile device (not shown), including, e.g., device2550. Each of such devices can contain one or more of computing device2500, 2550, and an entire system can be made up of multiple computingdevices 2500, 2550 communicating with each other.

Computing device 2550 includes processor 2552, memory 2564, aninput/output device including, e.g., display 2554, communicationinterface 2566, and transceiver 2568, among other components. Device2550 also can be provided with a storage device, including, e.g., amicrodrive or other device, to provide additional storage. Each ofcomponents 2550, 2552, 2564, 2554, 2566, and 2568, are interconnectedusing various buses, and several of the components can be mounted on acommon motherboard or in other manners as appropriate.

Processor 2552 can execute instructions within computing device 2550,including instructions stored in memory 2564. The processor can beimplemented as a chipset of chips that include separate and multipleanalog and digital processors. The processor can provide, for example,for coordination of the other components of device 2550, including,e.g., control of user interfaces, applications run by device 2550, andwireless communication by device 2550.

Processor 2552 can communicate with a user through control interface2558 and display interface 2556 coupled to display 2554. Display 2554can be, for example, a TFT LCD (Thin-Film-Transistor Liquid CrystalDisplay) or an OLED (Organic Light Emitting Diode) display, or otherappropriate display technology. Display interface 2556 can compriseappropriate circuitry for driving display 2554 to present graphical andother data to a user. Control interface 2558 can receive commands from auser and convert them for submission to processor 2552. In addition,external interface 2562 can communicate with processor 2542, so as toenable near area communication of device 2550 with other devices.External interface 2562 can provide, for example, for wiredcommunication in some implementations, or for wireless communication inother implementations, and multiple interfaces also can be used.

Memory 2564 stores data within computing device 2550. Memory 2564 can beimplemented as one or more of a computer-readable medium or media, avolatile memory unit or units, or a non-volatile memory unit or units.Expansion memory 2574 also can be provided and connected to device 2550through expansion interface 2572, which can include, for example, a SIMM(Single In Line Memory Module) card interface. Such expansion memory2574 can provide extra storage space for device 2550, or also can storeapplications or other data for device 2550. Specifically, expansionmemory 2574 can include instructions to carry out or supplement theprocesses described above, and can include secure data also. Thus, forexample, expansion memory 2574 can be provided as a security module fordevice 2550, and can be programmed with instructions that permit secureuse of device 2550. In addition, secure applications can be providedthrough the SIMM cards, along with additional data, including, e.g.,placing identifying data on the SIMM card in a non-hackable manner.

The memory can include, for example, flash memory and/or NVRAM memory,as discussed below. In one implementation, a computer program product istangibly embodied in a data carrier. The computer program productcontains instructions that, when executed, perform one or more methods,including, e.g., those described above. The data carrier is a computer-or machine-readable medium, including, e.g., memory 2564, expansionmemory 2574, and/or memory on processor 2552, which can be received, forexample, over transceiver 2568 or external interface 2562.

Device 2550 can communicate wirelessly through communication interface2566, which can include digital signal processing circuitry wherenecessary. Communication interface 2566 can provide for communicationsunder various modes or protocols, including, e.g., GSM voice calls, SMS,EMS, or MMS messaging, CDMA, TDMA, PDC, WCDMA, CDMA2000, or GPRS, amongothers. Such communication can occur, for example, throughradio-frequency transceiver 2568. In addition, short-range communicationcan occur, including, e.g., using a Bluetooth®, WiFi, or other suchtransceiver (not shown). In addition, GPS (Global Positioning System)receiver module 2570 can provide additional navigation- andlocation-related wireless data to device 2550, which can be used asappropriate by applications running on device 2550. Sensors and modulessuch as cameras, microphones, compasses, accelerators (for orientationsensing), etc. maybe included in the device.

Device 2550 also can communicate audibly using audio codec 2560, whichcan receive spoken data from a user and convert it to usable digitaldata. Audio codec 2560 can likewise generate audible sound for a user,including, e.g., through a speaker, e.g., in a handset of device 2550.Such sound can include sound from voice telephone calls, can includerecorded sound (e.g., voice messages, music files, and the like) andalso can include sound generated by applications operating on device2550.

Computing device 2550 can be implemented in a number of different forms,as shown in the figure. For example, it can be implemented as cellulartelephone 2580. It also can be implemented as part of smartphone 2582,personal digital assistant, or other similar mobile device.

Various implementations of the systems and techniques described here canbe realized in digital electronic circuitry, integrated circuitry,specially designed ASICs (application specific integrated circuits),computer hardware, firmware, software, and/or combinations thereof.These various implementations can include implementation in one or morecomputer programs that are executable and/or interpretable on aprogrammable system including at least one programmable processor, whichcan be special or general purpose, coupled to receive data andinstructions from, and to transmit data and instructions to, a storagesystem, at least one input device, and at least one output device.

These computer programs (also known as programs, software, softwareapplications or code) include machine instructions for a programmableprocessor, and can be implemented in a high-level procedural and/orobject-oriented programming language, and/or in assembly/machinelanguage. As used herein, the terms machine-readable medium andcomputer-readable medium refer to a computer program product, apparatusand/or device (e.g., magnetic discs, optical disks, memory, ProgrammableLogic Devices (PLDs)) used to provide machine instructions and/or datato a programmable processor, including a machine-readable medium thatreceives machine instructions.

To provide for interaction with a user, the systems and techniquesdescribed here can be implemented on a computer having a display device(e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor)for displaying data to the user and a keyboard and a pointing device(e.g., a mouse or a trackball) by which the user can provide input tothe computer. Other kinds of devices can be used to provide forinteraction with a user as well; for example, feedback provided to theuser can be a form of sensory feedback (e.g., visual feedback, auditoryfeedback, or tactile feedback); and input from the user can be receivedin a form, including acoustic, speech, or tactile input.

The systems and techniques described here can be implemented in acomputing system that includes a back end component (e.g., as a dataserver), or that includes a middleware component (e.g., an applicationserver), or that includes a front end component (e.g., a client computerhaving a user interface or a Web browser through which a user caninteract with an implementation of the systems and techniques describedhere), or a combination of such back end, middleware, or front endcomponents. The components of the system can be interconnected by a formor medium of digital data communication (e.g., a communication network).Examples of communication networks include a local area network (LAN), awide area network (WAN), and the Internet.

The computing system can include clients and servers. A client andserver are generally remote from each other and typically interactthrough a communication network. The relationship of client and serverarises by virtue of computer programs running on the respectivecomputers and having a client-server relationship to each other.

In some implementations, the engines described herein can be separated,combined or incorporated into a single or combined engine. The enginesdepicted in the figures are not intended to limit the systems describedhere to the software architectures shown in the figures.

1. A method comprising: collecting information related to one or moreconditions of a respiratory system associated with a patient;determining one or more control parameters based on the collectedinformation; and initiating a series of electric arcs external to thepatient to generate nitric oxide based on the determined controlparameters.
 2. The method of claim 1, wherein the conditions associatedwith the respiratory system include one or more of the oxygenconcentration of a reactant gas, a flow rate of the reactant gas, avolume and timing of an inspiration, the oxygen concentration of aproduct gas, the nitric oxide concentration of the product gas, thenitrogen dioxide concentration of the product gas, the ozoneconcentration of the product gas, the nitric oxide concentration of aninhaled gas, and the nitrogen dioxide concentration of the inhaled gas.3. The method of claim 1, wherein the volume and timing of aninspiration is received from a ventilator.
 4. The method of claim 1,wherein a pulse train initiates the series of electric arcs, the pulsetrain including pulse groups having pulses with different pulse widths.5. The method of claim 4, wherein the pulse width of initial pulses inone of the pulse groups is wider than other pulses in the pulse group.6. The method of claim 4, wherein the series of electric arcs generatesa reduced level of at least one of nitrogen dioxide or ozone. 7.(canceled)
 8. The method of claim 6, wherein the reduced level ofnitrogen dioxide is further reduced by a scavenger comprising one ormore of KaOH, CaOH, CaCO₃, and N_(a)OH.
 9. The method of claim 6,wherein the reduced level of nitrogen dioxide has a concentration thatis less than 20%, 10%, 6%, or 5% of a concentration of the generatednitric oxide.
 10. The method of claim 1, wherein the series of electricarcs is generated by electrodes comprising at least one of a noblemetal, iridium, or nickel.
 11. (canceled)
 12. (canceled)
 13. Anapparatus comprising: a chamber having an inlet valve for receiving areactant gas and an outlet valve for delivering a product gas; a sensorfor collecting information related to one or more conditions of arespiratory system associated with a patient; a controller fordetermining one or more control parameters based on the collectedinformation; and one or more pairs of electrodes positioned inside thechamber for initiating a series of electric arcs external to the patientto generate nitric oxide based on the determined control parameters. 14.The apparatus of claim 13, wherein the conditions associated with therespiratory system include one or more of the oxygen concentration ofthe reactant gas, a flow rate of the reactant gas, a volume and timingof an inspiration, the oxygen concentration of the product gas, thenitric oxide concentration of the product gas, the nitrogen dioxideconcentration of the product gas, the ozone concentration of the productgas, the nitric oxide concentration of an inhaled gas, the nitrogendioxide concentration of the inhaled gas, and the pressure in thechamber.
 15. The apparatus of claim 14, wherein the volume and timing ofan inspiration is received from a ventilator.
 16. The apparatus of claim13, wherein a pulse train initiates the series of electric arcs, thepulse train including pulse groups having pulses with different pulsewidths.
 17. The apparatus of claim 16, wherein the pulse width ofinitial pulses in one of the pulse groups is wider than other pulses inthe pulse group.
 18. The apparatus of claim 16, wherein the series ofelectric arcs generates a reduced level of at least one of nitrogendioxide or ozone.
 19. (canceled)
 20. The apparatus of claim 16, whereinthe series of electric arcs is initiated when the chamber has a pressuregreater than 1 ATA or less than 1 ATA.
 21. The apparatus of claim 18,further comprising a scavenger for further reducing the reduced level ofnitrogen dioxide, the scavenger comprising one or more of KaOH, CaOH,CaCO₃, and NaOH.
 22. The apparatus of claim 18, wherein the reducedlevel of nitrogen dioxide has a concentration that is less than 20%,10%, 6%, or 5% of a concentration of the generated nitric oxide.
 23. Theapparatus of claim 13, wherein the electrodes comprise at least one of anoble metal, iridium, or nickel.
 24. (canceled)
 25. (canceled)
 26. Theapparatus of claim 13, further comprising a piston positioned inside thechamber and configured to move along a length of the chamber foradjusting pressure in the chamber.
 27. (canceled)
 28. (canceled) 29.(canceled)
 30. (canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)34. (canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled) 38.(canceled)